| Inclusion criteria
Participants who are capable of giving signed informed consent as described in the protocol, which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in this protocol
• Participants (females, regardless of menopausal status, and males) who are age greater or equal to 18 years at the time of signing the Informed Consent Form
• Participants who have documented ER positive tumor by immunohistochemistry, as assessed locally on a primary disease specimen and defined as greater or equal to 1percent of tumor cells stained positive according to the ASCO/College of American Pathologists (CAP) guidelines (Allison et al. 2020).
• Participants who have documented HER2 negative tumor, as assessed locally on a primary disease specimen and defined according to ASCO/CAP guidelines (Wolff et al. 2018)
• Participants who have multicentric (the presence of two of more tumor foci within different quadrants of the same breast) and/or multifocal (the presence of two or more tumor foci within a single quadrant of the breast) breast cancer are also eligible if all examined tumors meet pathologic criteria for ER positivity and HER2 negativity
- Participants with bilateral synchronous invasive breast cancer are eligible if all histopathologically examined tumors meet pathologic criteria for ER positivity and HER2 negativity
• Participants must have undergone definitive surgery of the primary breast tumor(s). With the exception of the situations described below, the margins of the resected specimen must be histologically free of invasive tumor and/or a component of ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the participant must undergo mastectomy to be eligible. Of note, participants with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.
– For participants who undergo mastectomy or wide local excision where deep margin abuts the pectoralis fascia, participants with microscopic positive margins are eligible as long as radiotherapy of the chest wall is administered prior to study entry. Participants with positive anterior margins may be eligible if there is no gross disease left behind (radiotherapy as per local guidelines).
– Participants with suspected metastasis in supraclavicular or internal mammary nodes should be treated in accordance with standard local guidelines.
– If given, radiation therapy (e.g., post-mastectomy or post-lumpectomy) should be administered according to standard guidelines.
• Participants who received or will be receiving adjuvant chemotherapy must have completed adjuvant chemotherapy prior to randomization. Participants may also have received neoadjuvant chemotherapy. A washout period of at least 21 days is required between last adjuvant chemotherapy dose and randomization.
– Participants who are not candidates for adjuvant chemotherapy or decline chemotherapy are permitted.
Participants for whom resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade 1 or better (except alopecia, Grade less than or equal to 2 peripheral neuropathy, arthralgia, or other toxicities not considered a safety risk for the participant per the investigator’s judgment) • Participants have received (neo)adjuvant chemotherapy and/or had surgery and had no prior endocrine therapy are eligible, provided that they are enrolled within 12 months following definitive breast cancer surgery • Participants who have confirmed availability of an untreated primary breast tumor tissue specimen suitable for biomarker testing (i.e., representative archived formalin-fixed, paraffin-embedded [FFPE] tissue block [preferred] or 1520 slides containing unstained, freshly cut, serial sections), with associated de-identified pathology report is required. Although 1520 slides are preferred, if only 1014 slides are available, the individual may still be eligible for the study. – For eligibility determination on the basis of Ki67 score, a breast tumor tissue sample obtained prior to any exposure to systemic therapy must be submitted during screening for testing by a central pathology laboratory (see Section 8.7 for details on tumor tissue requirements)
Participants who received adjuvant chemotherapy or no chemotherapy must have the following:
– No pathological involved nodes (pN0) and primary tumor larger than 1 cm, and must fulfill at least one of the features as outlined in Table 5 (medium risk) – or
– Pathological node-positive disease (microscopic and/or macroscopic tumor involvement, ≥pN1) and will be stratified in medium or high risk based on criteria defined in Table 5
Participants with positive ipsilateral internal mammary and/or supraclavicular lymph nodes are stratified as high risk, irrespective of axillary nodal involvement.
• Participants who received neoadjuvant chemotherapy must have residual disease in lymph nodes (≥ypN1) after neoadjuvant chemotherapy and will be stratified to medium or high risk, based on disease characteristics outlined in Table 5
• Participants with T4 primary tumor and any N as outlined in Table 5 (high risk)
• Participant who have Eastern Cooperative Oncology Group Performance (ECOG) Performance Status 0, 1, or 2
• Participants who are able and willing to swallow, retain, and absorb oral medication • Participants who have adequate organ function as defined by the following criteria:
– ANC greater or equal to 1 109 /L (1000/L)
– Platelet count greater or equal to 75 109 /L (greater or equal to 75,000/L)
– AST and ALT less than or equal to 3 upper limit of normal (ULN)
– ALP less than or equal to 2.5 ULN
– Hemoglobin greater or equal to 80 g/L (greater or equal to 8 g/dL)
– Serum bilirubin less than or equal to 1.5ULN with the following exception: Participants with known Gilbert syndrome: less than or equal to 3ULN
– Glomerular filtration rate greater or equal to 60 mL/min and calculated per institutional guidelines
– INR less than 1.5 ULN and PTT(or aPTT) less than 1.5 ULN
For participants requiring anticoagulation therapy with warfarin, a stable INR between 2 and 3 is required.
For participants receiving heparin, PTT (or aPTT) between 1.5 and 2.5 ULN (or a participant’s value prior to starting heparin treatment) is required.
If anticoagulation therapy is required for a prosthetic heart valve, stable INR between 2.5 and 3.5 is permitted.
For women of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception (women assigned to tamoxifen must also agree to refrain from donating eggs), as defined below:
Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of less than 1percent per year during the treatment period and for 9 days after the final dose of giredestrant or within the time period specified per local prescribing guidelines after the final dose of TPC (i.e., 60 days after the final dose of tamoxifenwomen must refrain from donating eggs during this same period; 21 days after the final dose of letrozole or anastrozole; 30 days after the final dose of exemestane).
A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (greater or equal to 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of non-hormonal contraceptive methods with a failure rate of less than 1percent per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. Luteinizing hormonereleasing hormone agonists are not adequate contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
For men assigned: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 9 days after the final dose of giredestrant within the time period specified per local prescribing guidelines after the final dose of TPC (i.e., 90 days after the final dose of tamoxifen; 21 days after the final dose of letrozole or anastrozole; 30 days after the final dose of exemestane) to avoid exposing the embryo.
Additionally, for men receiving tamoxifen with female partners of childbearing potential, highly effective contraception should be used during treatment and for 90 days after final dose due to genotoxicity. Highly effective contraception may include vasectomy, abstinence, hormonal contraception in partner, bilateral tubal ligation in partner, or intrauterine device in partner. Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
• For participants enrolled in the extended China enrollment phase at NMPA recognized sites: participants who are current residents of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
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Exclusion
Participants are excluded from the study if any of the following criteria apply:
• Participants who are pregnant or breastfeeding or intending to become pregnant during the study or within 9 days after the final dose of giredestrant, or within the time period specified per local prescribing guidelines after the final dose of TPC. Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment and a negative urine pregnancy test within 24 hours prior to study treatment initiation.
• Participants who have received treatment with investigational therapy within 28 days prior to initiation of study treatment or is currently enrolled in any other type of medical research judged by the Sponsor not to be scientifically or medically compatible with this study
• Participants receiving or planning to receive a CDK4/6i as adjuvant therapy
• Participants who have active cardiac disease or history of cardiac dysfunction, including any of the following: – History (within 2 years of screening) or presence of idiopathic bradycardia or resting heart rate less than 50 beats per minute at screening – History of angina pectoris or symptomatic coronary heart disease within 12 months prior to randomization – History of documented congestive heart failure (New York Heart Association Class IIIV) or cardiomyopathy – QT interval corrected through use of Fridericia’s formula greater than 470 ms for women greater than 450 ms for men based on mean value of triplicate ECGs, history of long or short QT syndrome, Brugada syndrome or known history of corrected QT interval prolongation, or torsades de pointes – Presence of an abnormal ECG that is clinically significant in the investigator’s opinion, including complete left bundle branch block, second- or third-degree heart block, or sick sinus syndrome o Participants with first-degree heart block may be considered for inclusion following consultation with a cardiologist and determination that no additional cardiac risks are present. o Participants with pacemakers to treat more severe heart blocks and other arrhythmias are permitted.
• Patients with history of well-controlled atrial fibrillation are eligible. – History (within 12 months) or presence of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as significant structural heart disease (e.g., severe left ventricular systolic dysfunction, restrictive cardiomyopathy, hypertrophic cardiomyopathy, infiltrative cardiomyopathy, moderate-to-severe valve disease), or family history of long QT syndrome)
Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia) should be corrected prior to enrollment.
• Participants who have been diagnosed with Stage IV breast cancer
• Participants who have a history of any prior (ipsilateral and/or contralateral) invasive breast cancer or DCIS. Participants with a history of contralateral DCIS treated by only local regional therapy at any time may be eligible.
• Participants who have a history of any other malignancy within 3 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer. – For participants with a history of other non-breast cancers within 3 years from the date of randomization and considered of very low risk of recurrence per investigator’s judgment (e.g., papillary thyroid cancer treated with surgery), eligibility is to be discussed with the Sponsor
• Participants who have had any prior endocrine treatment with selective ER downregulators, degraders, or AI – Short course of neoadjuvant or adjuvant endocrine therapy (up to 4 weeks) is allowed. If the participant is currently receiving or initiating standard adjuvant endocrine therapy at the time of study entry, she/he may receive up to 4 weeks of endocrine therapy until randomization following the last non-endocrine therapy (surgery or chemotherapy), whichever is last
• Participants who have clinically significant liver disease consistent with Child-Pugh Class B or C, including active hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C virus [HCV]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis, as defined below: – Active infection is defined as requiring treatment with antiviral therapy or presence of positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B core antibody [HBcAb]) or HCV antibody. Unless required by local regulations, participants are not required to have HBV or HCV assessments at screening if these assessments have not been previously performed. – Participants who test positive for HBcAb are eligible only if test results are also positive for hepatitis B surface antibody and polymerase chain reaction is negative for HBV DNA – Participants who are positive for HCV serology are eligible only if testing for HCV RNA is negative
• Participants who have a known allergy or hypersensitivity to any of the study drugs or any of their excipients
• Pre- and perimenopausal participants or male participants who have a known hypersensitivity to LHRH agonists
• Participants who have a documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism
Participants who have had a major surgical procedure unrelated to breast cancer within 28 days prior to randomization
• Participants who have had a serious infection requiring oral or IV antibiotics within 14 days prior to screening or other clinically significant infection (e.g., COVID-19) within 14 days prior to screening Participants who have fully recovered from serious or clinically significant infections at least 14 days prior to screening are eligible. If a participant exhibits signs or symptoms of potential COVID-19 infection and there is a reasonable suspicion of exposure, investigators are to follow the ASCO 2020 guidelines or institutional guidelines on testing.
• Participants who have had any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study
• Participants who are unable or unwilling to comply with the requirements of the protocol in the opinion of the investigator
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80 and over: 80+ Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) |
18 Year(s) |
100 Year(s) |
Both |